脑微透析在药物监测中的应用

脑微透析是一种微创取样技术,具有多位点、实时取样和可在线等优点,在脑部药物监测中越来越受到关注。脑微透析技术为脑部药物浓度的监测提供了一种有效的新途径,可为新药研发与临床合理用药提供科学依据,在脑部给药系统研究中,特别是药动学及药效学研究中优势显著,具有很好的应用前景。本文综述了有关脑部微透析技术的特点及发展,介绍了脑微透析技术在药物监测研究中的进展,分别归纳了微透析技术在实验动物和临床患者中的应用情况。     

微透析技术用于化疗药物——吉西他滨体内药动学的初步研究

目的：建立以微透析法（microdialysis,MD）为采样技术的肿瘤化疗药物在体检测方法,并进行药动学研究。方法：以吉西他滨（GEM）为研究对象,大鼠为实验动物,采用尾静脉注射为给药方式,通过微透析技术进行血管内取样,对血药浓度进行在线、实时、连续监测,求算相关药动学参数。结果：GEM在大鼠体内血液中的探针回收率为（11.9±2.0）%,经大鼠尾静脉给药后GEM体内过程为二室模型,其消除和分布为一级动力学过程。实验过程中大鼠未见明显副作用。结论：微透析技术可用于活体动物体内GEM浓度的连续监测,提示微透析技术可用于抗肿瘤药物的局部药动学研究。     

微透析技术在靶组织局部药物浓度检测中的应用

微透析技术是一项越来越被广泛使用的在体研究技术,其遵循透析原理,以探针为基础取样,可连续检测局部组织细胞外液的药物浓度,能满足常规的药代动力学/药效学(PK-PD)研究。本文就其在靶组织局部药物浓度检测中的应用作一简要介绍。     

微透析技术在药物代谢和药代动力学研究中的应用

本文介绍了近年来有关微透析技术在药物代谢和药动学研究领域中应用的现状入已取得重大进展。微透析技术除应用于动物模型中的研究外,在人体中的研究特别是临床应用方面亦在发展中,该项技术在药物代谢和药代动力学研究领域中有广阔应用前景,但微透析探针校正和对微透析取样获得的少量样品的分析方法是仍需要深入研究的问题。     

微透析技术在神经重症监护中的研究进展

微透析技术（microdialysis，MD）是1种活体细胞外液生化物质采样分析技术。因其独有的微创性和取样的连续性，现已被广泛应用于脑组织各种病理生理现象的探索性实验、神经生物化学的监测和药物代谢研究。近来，甚至被用于局部的治疗性给药。1966年，Bito等闭首次使用MD将1张灌有液体的半透膜置入犬体内进行实验。自1972年美国耶鲁大学首次报道了猴脑的微透析研究，微透析技术用于脑部研究已有30多年。     

微透析采样技术在抗乳腺癌药物研究方面的应用

目的:介绍微透析采样技术在抗乳腺癌药物方面的研究与应用现状。方法:参阅国内外文献,进行分析、归纳和总结。结果:微透析采样技术在乳腺癌的发病机制、乳腺癌药物临床前和临床药理及药动学、PK-PD结合模型、联合用药合理性等方面研究应用广泛。结论:微透析采样技术结合现代成像技术,在乳腺癌肿瘤局部药动学研究方面具有广阔的应用前景。     

微透析取样技术及其在药代动力学中的应用

本文综述了近年来国外有关微透析取样技术在药代动力学中的应用，介绍了微透析取样技术的原理、组成以及微透析探针的类型，重点介绍了在体微透析取样技术在动物和人药代动力学中的应用。表明微透析取样技术在药代动力学中的应用具有广阔的前景。     

微透析取样技术及其在体内药物分析中的应用

通过查阅近几年的相关文献，并结合本实验室的相关研究，概述了微透析取样技术的原理和优势，重点介绍了其在体内药物分析中的应用。微透析取样技术能直接对作用部位细胞外液中的药物及其代谢产物进行取样，是体内药物分析的重要工具。此技术在体内药物分析领域具有广阔的应用前景。     

微透析技术在抗菌药物药动学和药效学中的应用

微透析技术是一项新兴的体内药物分析技术。通过微透析技术与药动学和药效学模型结合,实现对组织或细胞外游离态药物浓度及其相应药理效应的同时研究,不仅有利于进一步明确药物的剂量-效应关系,制定临床最佳给药方案,而且也为个体化给药提供了科学依据。本文综合近年文献,对微透析技术的基本原理以及在抗菌药物药动学和药效学研究中的应用作一综述。     

微透析技术在药物-蛋白结合研究中的应用

目的 介绍微透析技术在药物-蛋白结合研究中的应用。方法 通过查阅近年来国内外相关文献,概述微透析技术的基本原理、特点、探针及影响探针相对回收率的主要因素,并重点介绍其在药物-蛋白结合研究中的应用。结果与结论 与平衡透析法、超滤法相比,微透析技术是一项新兴的在体或离体取样技术,在药物-蛋白结合研究中具有显著的优越性和广阔的应用前景。     

MRI-Guided Monitoring of Thermal Dose and Targeted Drug Delivery for Cancer Therapy

Application of localized hyperthermia treatment for solid tumor therapy is under active clinical investigation. The success of this treatment methodology, whether for tumor ablation or drug delivery, requires accurate target localization and real-time temperature mapping of the targeted region. Magnetic Resonance Imaging (MRI) can monitor temperature elevations in tissues in real-time during tumor therapy. MRI can also be applied in concert with methods such as High Intensity Focused Ultrasound (HIFU) to enable image-guided drug delivery (IGDD) from temperature sensitive nanocarriers, by exploiting not only its anatomic resolution, but its ability to detect and measure drug release using markers co-loaded with drugs within the nanocarriers. We review this rapidly emerging technology, providing an overview of MRI-guided tissue thermal dose monitoring for HIFU and Laser therapy, its role in targeted drug delivery and its future potential for clinical translation.     

Microdialysis for the evaluation of penetration through the human skin barrier — a promising tool for future research?

The direct measurement of local drug concentration levels at discreet skin locations with minor trauma has recently become possible with the introduction of cutaneous microdialysis. Cutaneous microdialysis is an in vivo sampling technique for measuring solutes in the extracellular fluid of the dermis. When used in combination with other experimental approaches, for example with a variety of non-invasive techniques to describe the functional status of the skin (bioengineering methods), it may help investigators to gain new insights into the fields of skin diseases, metabolism and drug absorption/penetration. An important parameter to describe the efficacy of microdialysis is the relative recovery. This is the ratio between the concentration of a substance in the dialysate and the true extracellular concentration. Several methods are in common use to describe the relative recovery (no-net-flux method or retrodialysis). Parameters such as probe design, depth of the probe in the dermis, physico-chemical properties of the compound of interest, and analytical aspects are important factors influencing microdialysis. Microdialysis has been used to investigate the influence of penetration enhancers, vehicles or iontophoresis on percutaneous absorption, performed by in vivo studies in rats. In human volunteers, most of the experiments have been performed to study the kinetics of fast penetrating substances, e.g. nicotine, non-steroidal antiinflammatory drugs, local anaesthetics, or solvents. Problems have been encountered in the detection of lipophilic and highly protein-bound substances. Further, dermal metabolism and the influence of barrier perturbation on percutaneous absorption have been analyzed. Investigations suggest that microdialysis, in combination with traditional techniques, might give valuable information regarding the assessment of the penetration of drugs and other exogenous agents through the skin. In spite of the clearly defined and accepted advantages of microdialysis technology for studies of transdermal drug delivery, to date no standardized test procedure exists nor has the reproducibility of the results been evaluated. In the future, these problems have to be solved to enable this method to find its place in standard research.     

Assessment of cutaneous drug delivery using microdialysis

During the last decade microdialysis has been successfully applied to assess cutaneous drug delivery of numerous substances, indicating the large potential for bioequivalence/bioavailability evaluation of topical formulations. The technique has been shown to be minimally invasive and supply pharmacokinetic information directly in the target organ for cutaneous drug delivery with high temporal resolution without further intervention with the tissue after implantation. However, there are a few challenges that need to be addressed before microdialysis can be regarded as a generally applicable routine technique for cutaneous drug delivery assessments. Firstly, the technique is currently not suitable for sampling of highly lipophilic compounds and, secondly, more studies are desirable for elucidation of the variables associated with the technique to increase reproducibility. The present literature indicates that the condition of the skin at the individual assessment sites is the main variable, but also variables associated with relative recovery, differentiation between the pharmacokinetic parameters (i.e., lag time, distribution, absorption and elimination rate) can influences the reproducibility of the technique. Furthermore, it has been indicated that cutaneous microdialysis in rats may be useful for prediction of dermal pharmacokinetic properties of novel drugs/topical formulations in man.     

Cerebral microdialysis in clinical studies of drugs: pharmacokinetic applications

The ability to deliver drug molecules effectively across the blood–brain barrier into the brain is important in the development of central nervous system (CNS) therapies. Cerebral microdialysis is the only existing technique for sampling molecules from the brain extracellular fluid (ECF; also termed interstitial fluid), the compartment to which the astrocytes and neurones are directly exposed. Plasma levels of drugs are often poor predictors of CNS activity. While cerebrospinal fluid (CSF) levels of drugs are often used as evidence of delivery of drug to brain, the CSF is a different compartment to the ECF. The continuous nature of microdialysis sampling of the ECF is ideal for pharmacokinetic (PK) studies, and can give valuable PK information of variations with time in drug concentrations of brain ECF versus plasma. The microdialysis technique needs careful calibration for relative recovery (extraction efficiency) of the drug if absolute quantification is required. Besides the drug, other molecules can be analysed in the microdialysates for information on downstream targets and/or energy metabolism in the brain. Cerebral microdialysis is an invasive technique, so is only useable in patients requiring neurocritical care, neurosurgery or brain biopsy. Application of results to wider patient populations, and to those with different pathologies or degrees of pathology, obviously demands caution. Nevertheless, microdialysis data can provide valuable guidelines for designing CNS therapies, and play an important role in small phase II clinical trials. In this review, we focus on the role of cerebral microdialysis in recent clinical studies of antimicrobial agents, drugs for tumour therapy, neuroprotective agents and anticonvulsants.     

Microdialysis: current applications in clinical pharmacokinetic studies and its potential role in the future

Microdialysis is a probe-based sampling method, which, if linked to analytical devices, allows for the measurement of drug concentration profiles in selected tissues. During the last two decades, microdialysis has become increasingly popular for preclinical and clinical pharmacokinetic studies. The advantage of in vivo microdialysis over traditional methods relates to its ability to continuously sample the unbound drug fraction in the interstitial space fluid (ISF). This is of particular importance because the ISF may be regarded as the actual target compartment for many drugs, e.g. antimicrobial agents or other drugs mediating their action through surface receptors. In contrast, plasma concentrations are increasingly recognised as inadequately predicting tissue drug concentrations and therapeutic success in many patient populations. Thus, the minimally invasive microdialysis technique has evolved into an important tool for the direct assessment of drug concentrations at the site of drug delivery in virtually all tissues. In particular, concentrations of transdermally applied drugs, neurotransmitters, antibacterials, cytotoxic agents, hormones, large molecules such as cytokines and proteins, and many other compounds were described by means of microdialysis. The combined use of microdialysis with non-invasive imaging methods such as positron emission tomography and single photon emission tomography opened the window to exactly explore and describe the fate and pharmacokinetics of a drug in the body. Linking pharmacokinetic data from the ISF to pharmacodynamic information appears to be a straightforward approach to predicting drug action and therapeutic success, and may be used for decision making for adequate drug administration and dosing regimens. Hence, microdialysis is nowadays used in clinical studies to test new drug candidates that are in the pharmaceutical industry drug development pipeline.     

Development of an in vitro dissolution method using microdialysis sampling technique for implantable drug delivery systems.

The major challenge faced during the development of implantable dosage forms for site-specific delivery is monitoring the local concentration of the drug at or around the site of action. The tissue concentration at the site is generally measured by either sacrificing the animal at different points in time or by determining the amount of drug left in the implants at various time intervals. Unfortunately, there are no official in vitro dissolution methods available to study the release characteristics of drugs from this drug delivery system. The objective of this investigation was to develop a simple method using microdialysis sampling technique to serve as an in vitro dissolution method for implantable drug delivery systems. Ciprofloxacin implants were prepared by compressing ciprofloxacin microcapsules in poly(lactic acid) (PLA) and poly(lactic-glycolic acid) (PLGA). A sensitive HPLC method was developed and validated for the assay of Ciprofloxacin. An in vitro dissolution method was developed to study the release characteristics of drug from these implants. The method used a microdialysis sampling technique and a small sample volume of release medium. The various advantages and disadvantages of this method over other USP methods are discussed.     

Microdialysis as a tool in local pharmacodynamics

In many cases the clinical outcome of therapy needs to be determined by the drug concentration in the tissue compartment in which the pharmacological effect occurs rather than in the plasma. Microdialysis is an in vivo technique that allows direct measurement of unbound tissue concentrations and permits monitoring of the biochemical and physiological effects of drugs throughout the body. Microdialysis was first used in pharmacodynamic research to study neurotransmission, and this remains its most common application in the field. In this review, we give an overview of the principles, techniques, and applications of microdialysis in pharmacodynamic studies of local physiological events, including measurement of endogenous substances such as acetylcholine, catecholamines, serotonin, amino acids, peptides, glucose, lactate, glycerol, and hormones. Microdialysis coupled with systemic drug administration also permits the more intensive examination of the pharmacotherapeutic effect of drugs on extracellular levels of endogenous substances in peripheral compartments and blood. Selected examples of the physiological effects and mechanisms of action of drugs are also discussed, as are the advantages and limitations of this method. It is concluded that microdialysis is a reliable technique for the measurement of local events, which makes it an attractive tool for local pharmacodynamic research.     

Application of microdialysis to characterize drug disposition in tumors

Microdialysis is an in vivo sampling technique that was initially developed to measure endogenous substances in the field of neurotransmitter research. In the past decade, microdialysis has been increasingly applied to study the pharmacokinetics and drug metabolism in the blood and various tissues of both animals and humans. This paper describes the general aspects of this in vivo sampling technique followed by the survey of the recent papers regarding the application of microdialysis to characterize anticancer drug disposition in solid tumors. It can be concluded that microdialysis is a very suitable method to obtain drug concentration-time profiles in the interstitial fluid of solid tumors as well as of other variety of tissues.     

Applicability of reverse microdialysis in pharmacological and toxicological studies

A recent application of microdialysis is the introduction of a substance into the extracellular space via the microdialysis probe. The inclusion of a higher amount of a drug in the perfusate allows the drug to diffuse through the microdialysis membrane to the tissue. This technique, actually called as reverse microdialysis, not only allows the local administration of a substance but also permits the simultaneous sampling of the extracellular levels of endogenous compounds. Local effects of exogenous compounds have been studied in the central nervous system, hepatic tissue, dermis, heart and corpora luteae of experimental animals by means of reverse microdialysis. In central nervous studies, reverse microdialysis has been extensively used for the study of the effects on neurotransmission at different central nuclei of diverse pharmacological and toxicological agents, such as antidepressants, antipsychotics, antiparkinsonians, hallucinogens, drugs of abuse and experimental drugs. In the clinical setting, reverse microdialysis has been used for the study of local effects of drugs in the adipose tissue, skeletal muscle and dermis. The aim of this review is to describe the principles of the reverse microdialysis, to compare the technique with other available methods and finally to describe the applicability of reverse microdialysis in the study of drugs properties both in basic and clinical research.